{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:03:39Z","timestamp":1789419819620,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study aims to investigate the associations between genetically proxied JAK inhibition and various disease outcomes and adverse effects, providing insights into therapeutic efficacy and potential side effects for immune-mediated skin diseases (IMIDs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using Mendelian Randomization (MR), we analyzed genetic proxies for JAK1, JAK2, JAK3, and TYK2 inhibition. Data from the UK Biobank (N = 361,194) and FinnGen (N = 453,733) were utilized to explore associations with nine autoimmune skin diseases, and twelve adverse outcomes, including tuberculosis, non-melanoma skin cancer, lung cancer, and pulmonary embolism. A systematic review of randomized controlled trials (RCTs) on JAK inhibitors in IMIDs was performed to complement the genetic evidence, focusing on safety outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Summary-data-based MR (SMR) analysis revealed that genetically proxied loss of function mutation of TYK2 was linked to psoriasis (OR = 0.673, 95% CI = 0.512\u20130.884, p = 0.004), aligning with clinical evidence. Safety analyses yielded genetically supported, hypothesis-generating signals with effect sizes close to unity, including associations between JAK2 inhibition and pulmonary embolism (OR = 0.998, p = 0.035) and tuberculosis (OR = 1.004, p = 0.013), as well as TYK2 inhibition and malignant non-melanoma skin cancer (OR = 1.006, p = 0.047), and lung cancer (OR = 1.002, p = 0.029). These findings should be interpreted cautiously and do not constitute definitive evidence of drug-induced adverse effects. The systematic review partially confirmed the safety of JAK inhibitors in IMIDs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study supports TYK2 inhibition as a targeted therapy for psoriasis and provides hypothesis-generating genetic evidence for additional target\u2013disease and target\u2013safety associations that warrant further validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1738089","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:48:16Z","timestamp":1773902896000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic pharmacoepidemiology of JAK inhibitors in chronic immune-mediated skin diseases: implications for precision therapy and medication safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuping","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qundi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibo","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaomu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.3390\/ph15010048","article-title":"Jakinibs of all trades: inhibiting cytokine signaling in immune-mediated pathologies","volume":"15","author":"Alexander","year":"2021","journal-title":"Pharm. 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